Steroid receptors antagonists are used for a variety of clinical purposes including treatment of breast cancer and other hormone- dependent tumors. It has become increasingly apparent that the cellular level of the steroid receptor and the antagonist are not the only factors that determine biological response. Steroid receptor interaction with co-regulatory proteins such as co-activators, co-repressors and other transcription factors are important determinants of the final receptor activity. Because steroid receptor antagonists exhibit varying degrees of hormone agonist activity dependent on cell/tissue type and physiological state of the cell, we hypothesize that the relative agonist/antagonist activity exhibited by these compounds is controlled by the cellular level of expression, or availability, of these other receptors interacting proteins. The overall goal of this research is to identify functionally important receptor-interacting proteins and protein complexes that contribute to steroid antagonists behaving as effective antagonists in some cell/tissue types and physiological states, and as hormone agonists in others. Our research will focus on progesterone receptor (PR) and progesterone antagonists. We expect that many of the fundamental mechanisms discovered with PR will apply to other receptors such as estrogen (ER), androgen (AR) and glucocorticoid receptors (GR). AIM #1 of the proposal will biochemically isolate and identify functionally important receptor interacting co-activator and co-repressor interacting co-activator and co-repressor complex that correlate with antagonists exhibiting partial agonist activity in different cell types and under different physiological states. AIM #2 will use a genetic screening strategy to identify other receptor interacting co-regulatory proteins involve din mediating hormone agonist activities of antagonists. AIM #3 will investigate how steroid antagonists alter receptor interaction with specific co-regulatory proteins to either successfully inactive the receptor or leave it in an active state. AIM #4 will determine how steroid antagonists influence receptor interaction with other physiologically important gene regulatory proteins. As an example of this mode of regulation, PR co- expression of STAT5 (signal transducers and activators of transcription) mediated activation of milk protein gene expression will be investigated. An understanding of steroid receptor antagonist action at this mechanistic level is anticipated to help in the design of new receptor antagonists (or hormone mimics) that will elicit the desired cell/tissue specific therapeutic response without adverse responses in other tissues.